Abstract
Drugs of abuse, including alcohol, ablate the expression of specific forms of long-term synaptic depression (LTD) at glutamatergic synapses in dorsal striatum (DS), a brain region involved in goal-directed and habitual behaviors. This loss of LTD is associated with altered DS-dependent behavior. Given the role of the µ-opioid receptor (MOR) in behavioral responding for alcohol, we explored the impact of alcohol on various forms of MOR-mediated synaptic depression that we find are differentially expressed at specific DS synapses. Corticostriatal MOR-mediated LTD (mOP-LTD) in the dorsolateral striatum occurs exclusively at inputs from anterior insular cortex and is selectively disrupted by in vivo alcohol exposure. Alcohol has no effect on corticostriatal mOP-LTD in dorsomedial striatum, thalamostriatal MOR-mediated short-term depression, or mOP-LTD of cholinergic interneuron-driven glutamate release. Disrupted mOP-LTD at anterior insular cortex–dorsolateral striatum synapses may therefore be a key mechanism of alcohol-induced neuroadaptations involved in the development of alcohol use disorders.
Highlights
Drugs of abuse, including alcohol, ablate the expression of specific forms of long-term synaptic depression (LTD) at glutamatergic synapses in dorsal striatum (DS), a brain region involved in goal-directed and habitual behaviors
The current study confirmed previously established mOP-LTD in DLS2 (Fig. 1) and demonstrates that it occurs in mouse dorsomedial striatum (DMS) as well (Fig. 1)
most selectively at μ-opioid receptors (MORs)-mediated inhibition of glutamate release could occur at three distinct synapse types in the DS: the glutamatergic inputs from cortex or thalamus, or driven by cholinergic interneurons (CINs) activation[9]
Summary
Drugs of abuse, including alcohol, ablate the expression of specific forms of long-term synaptic depression (LTD) at glutamatergic synapses in dorsal striatum (DS), a brain region involved in goal-directed and habitual behaviors. This loss of LTD is associated with altered DS-dependent behavior. We use a combination of mouse brain slice electrophysiology, in vivo EtOH exposure, optogenetics, and conditional MOR knockout mice to probe MOR-mediated synaptic plasticity at the three sources of glutamatergic input to MSNs (cortical, thalamic, and CIN inputs) in the DS Using these tools, we demonstrate that in vivo EtOH exposure persistently and interferes with corticostriatal mOP-LTD exclusively within the DLS.
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